Zero vergence ultrasound waves for sonodynamic therapy

Abstract

Disclosed are methods of obtaining zero vergence ultrasound waves for providing sonodynamic therapy with ultrasound waves that do not converge and do not diverge. The method includes coupling a sonodynamic therapy device with an array of flat piezoelectric transducers to a skin surface. A controller is configured to generate an electrical drive signal at a frequency, modulate the drive signal, and drive the transducer with the modulated drive signal at the frequency to produce a zero vergence ultrasound wave to produce an average acoustic intensity sufficient to activate a sonosensitizer in a treatment region without damaging healthy cells in the treatment region.

What is claimed is: 
     
       1. A method of obtaining zero vergence ultrasound waves for sonodynamic therapy to treat tumor cells harboring a sonosensitizer, comprising:
 coupling a sonodynamic therapy device to a skin surface of a head of a patient with a brain with the tumor cells, the sonodynamic therapy device comprising a flexible membrane coupled to a rigid shell and a cooling system,
 wherein the rigid shell comprises an array of flat piezoelectric ultrasound transducers and a controller, 
 wherein each of the flat piezoelectric ultrasound transducers is configured to emit a zero vergence ultrasound wave, 
 wherein the zero vergence ultrasound wave does not converge, 
 wherein the zero vergence ultrasound wave does not diverge; 
 
 driving the array of flat piezoelectric ultrasound transducers with a signal to activate the sonosensitizer in the tumor cells of the patient,
 wherein the sonosensitizer comprises protoporphyrin IX, 
 wherein the signal is configured to minimize a spatial variation of an acoustic intensity in the brain with the tumor cells of the patient with a modulated wave parameter to emit the zero vergence ultrasound wave with the acoustic intensity to activate the protoporphyrin IX in a treatment region to treat cancer in the tumor cells of the patient, 
 wherein the signal is modulated by a frequency modulated drive signal to produce a frequency modulated acoustic wave with a variety of frequencies in a range of 650 kHz to 2 MHz configured to minimize the spatial variation of the acoustic intensity in the brain at the tumor cells of the patient when activating the protoporphyrin IX, 
 wherein the sonodynamic therapy device is configured to acoustically couple the array of flat piezoelectric ultrasound transducers to the skin surface, 
 wherein the flexible membrane is configured for conforming to the head of the patient at the skin surface; 
 wherein the driving the array of flat piezoelectric transducers comprises phase randomization to promote broad consistent coverage of the treatment region by a plurality of the zero vergence ultrasound waves, 
 wherein the array of flat piezoelectric ultrasound transducers comprises a grid of concentric elements, and 
 
 circulating a fluid in the cooling system to reduce heat at the skin surface. 
 
     
     
       2. The method of  claim 1 ,
 wherein the controller determines at least one in situ variable selected from the group consisting of: a tissue depth, a tissue volume, a skull thickness, and a temperature, and adaptively modulates the modulated wave parameter to generate the zero vergence ultrasound wave optimized based on the at least one in situ variable. 
 
     
     
       3. The method of  claim 1 , wherein the controller determines an in situ variable and adaptively modulates the zero vergence ultrasound wave to preferentially target the treatment region based on the in situ variable. 
     
     
       4. The method of  claim 1 , wherein the controller detects at least one flat piezoelectric transducer in the array of flat piezoelectric transducers and selects a treatment algorithm for the at least one flat piezoelectric transducer. 
     
     
       5. The method of  claim 1 ,
 wherein the signal comprises at least one of the group consisting of: an intra pulse variation and an inter pulse variation. 
 
     
     
       6. The method of  claim 1 , wherein the controller drives the array of flat piezoelectric transducers with the signal at the variety of frequencies, to emit the zero vergence ultrasound wave with a temporal average intensity without causing thermal or other damage to healthy cells in the treatment region. 
     
     
       7. The method of  claim 1 , wherein the controller drives the array of flat piezoelectric transducers with the signal at the variety of frequencies, to emit the zero vergence ultrasound wave for a non-thermally ablative treatment with a temporal average intensity without increasing a temperature of a healthy tissue in the treatment region above 42° C. 
     
     
       8. The method of  claim 1 , further comprising:
 measuring a temperature with a temperature sensor in the cooling system; and 
 varying the signal based on the temperature, 
 wherein the cooling system comprises the temperature sensor and an elastic, fluid-filled pocket between the flexible membrane and the rigid shell, wherein the fluid is water, and 
 wherein the driving the array of flat piezoelectric ultrasound transducers comprises driving multiple concentric elements with multiple signals. 
 
     
     
       9. A method of obtaining zero vergence ultrasound waves for sonodynamic therapy to treat tumor cells harboring a sonosensitizer, comprising:
 coupling a sonodynamic therapy device to a skin surface of a head of a patient, the sonodynamic therapy device comprising a flexible membrane coupled to a rigid shell and a cooling system,
 wherein the rigid shell comprises an array of flat piezoelectric ultrasound transducers and a controller, 
 wherein each of the flat piezoelectric ultrasound transducers is configured to emit a zero vergence ultrasound wave, 
 wherein the zero vergence ultrasound wave does not converge, 
 wherein the zero vergence ultrasound wave does not diverge; 
 
 driving the array of flat piezoelectric ultrasound transducers with a signal to activate the sonosensitizer in the tumor cells in a brain of the patient,
 wherein the sonosensitizer comprises protoporphyrin IX, 
 wherein the signal is configured to minimize a spatial variation of an acoustic intensity in the brain with the tumor cells of the patient with a modulated wave parameter configured to emit a plurality of the zero vergence ultrasound waves with a frequency in a range of 650 kHz to 2 MHz at the acoustic intensity in a range of 0.1 W/cm 2  to 50 W/cm 2  to activate the protoporphyrin IX in a treatment region to treat cancer in the tumor cells of the patient, 
 wherein the signal is modulated by a duty cycle modulated drive signal configured to produce a duty cycle modulated acoustic wave, wherein the duty cycle modulated drive signal is configured to generate a high temporal peak acoustic intensity of the zero vergence ultrasound wave with a low temporal average acoustic intensity when activating the protoporphyrin IX, 
 wherein the sonodynamic therapy device is configured to acoustically couple the array of flat piezoelectric ultrasound transducers to the skin surface, 
 wherein the flexible membrane is configured for conforming to the head of the patient at the skin surface; and 
 
 circulating a fluid in the cooling system to reduce heat at the skin surface. 
 
     
     
       10. The method of  claim 9 , further comprising:
 measuring a temperature with a temperature sensor in the cooling system coupled to the array of flat piezoelectric transducers; and 
 varying the signal based on the temperature, 
 wherein the cooling system comprises the temperature sensor and an elastic pocket between the flexible membrane and the array of flat piezoelectric transducers, 
 wherein driving the array of flat piezoelectric ultrasound transducers comprises driving multiple concentric elements with multiple signals. 
 
     
     
       11. The method of  claim 9 , wherein the controller drives the array of flat piezoelectric transducers with the signal at the frequency to emit the zero vergence ultrasound wave with the temporal average acoustic intensity without increasing a temperature of a healthy tissue in the treatment region above 42° C. 
     
     
       12. The method of  claim 9 , wherein the signal is a packet comprising a predetermined number of cycles per packet to produce a packet of acoustic waves, the signal being selected from at least one of the group consisting of: a frequency modulated drive signal and a phase modulated signal. 
     
     
       13. The method of  claim 12 , wherein the packet is made of a repeating signal comprising at least one selected from the group consisting of: a sine wave, a rectangular pulse, and a triangular pulse. 
     
     
       14. The method of  claim 1 , wherein the zero vergence ultrasound wave is a planar wave. 
     
     
       15. The method of  claim 1 , wherein the signal is further modulated by a duty cycle modulated drive signal configured to produce a duty cycle modulated acoustic wave, wherein the duty cycle modulated drive signal is configured to generate a temporal average acoustic intensity when activating the protoporphyrin IX. 
     
     
       16. The method of  claim 1 , further comprising circulating a fluid through a cooling channel in the cooling system to reduce heat at the skin surface of the head of the patient at the flexible membrane. 
     
     
       17. The method of  claim 16 , wherein the fluid is configured to acoustically couple the array of flat piezoelectric ultrasound transducers to the flexible membrane. 
     
     
       18. The method of  claim 9 , wherein the zero vergence ultrasound wave is a planar wave. 
     
     
       19. The method of  claim 9 , further comprising circulating a fluid through a cooling channel in the cooling system to reduce heat at the skin surface of the head of the patient at the flexible membrane, wherein the fluid is configured to acoustically couple the array of flat piezoelectric ultrasound transducers to the flexible membrane.